Melanin extinguisher

ABSTRACT

A melanin eliminator preparation comprising a metal chelate compound represented by the following formula (I),  
                 
wherein M denotes a metal, and R denotes hydroxyl, O-lower alkyl, an amine bonded at N, an amino acid bonded at N, or a peptide bonded at N, or a pharmacologically acceptable salt thereof.

TECHNICAL FIELD

The present invention relates to a novel and useful melanin eliminatorpreparation comprising a 6,8-dimercaptooctanoic acid metal chelatecompound, derivatives thereof or pharmacologically acceptable saltsthereof.

BACKGROUND ART

6,8-dimercaptooctanoic acid is the reduced form of α-lipoic acid, acoenzyme occurring in mitochondria, and has an ability of restoringreduced forms of glutathione or vitamin C back from their oxidizedforms. However, 6,8-dimercaptooctanoic acid is so unstable in the airthat it is oxidized back to α-lipoic acid.

A group of α-lipoylamino acids are described in Japanese PatentPublication No. S42-1286 (corresponding U.S. Pat. No. 3,238,224), inwhich glycine, methionine, glutamic acid, valine or the like,respectively, is bonded to α-lipoic acid.

An imidazole salt of α-lipoylaminoethylsulfonic acid is described inExample 24 in Japanese Patent Application Publication No. 2000-169371.

A pharmaceutical preparation for external use containing a lipoamide asan active ingredient is disclosed in Japanese Patent ApplicationPublication No. S63-8316.

Other lipoic acid derivatives such as lipoyl esters are also known(Biochem. J. (1990) 271, 45-49).

Further, metal derivatives of dihydrolipoic acid and dihydrolipoamideare also known (Inorganica Chimica Acta, 192 (1992) 237-242) (J. Org.Chem. 1985, 50 2522-2524).

In the abovementioned situation, the present inventor found as a resultof repeated studies that 6,8-dimercaptooctanoic acid metal chelatecompounds, derivatives thereof and pharmacologically acceptable saltsthereof have a melanin eliminating effect, i.e., that simple externalapplication of the present compound to the skin under which aggregatedmelanin pigment is deposited, eliminates melanin without giving anydamage to the skin, thus completed the present invention.

The present invention provides a melanin eliminator preparationcomprising a 6,8-dimercaptooctanoic acid metal chelate compound, aderivative thereof or a pharmacologically acceptable salt thereof.

DISCLOSURE OF INVENTION

The present invention relates to:

a melanin eliminator preparation comprising a metal chelate (or a metalcomplex) compound represented by the following formula (I) (hereinafteralso referred to as “the present compound”),

wherein M denotes a metal, and R denotes hydroxyl, O-lower alkyl, anamine bonded at N, an amino acid bonded at N, or a peptide bonded at N,or a pharmacologically acceptable salt thereof.

(2) The melanin eliminator preparation defined in (1) above wherein themetal chelate compound is 6,8-dimercaptooctanoic acid metal chelatecompound.

(3) The melanin eliminator preparation defined in (1) above wherein themetal chelate compound is a 6,8-dimercaptooctanoic acid lower alkylester metal chelate compound.

(4) The melanin eliminator preparation defined in (3) above wherein the6,8-dimercaptooctanoic acid lower alkyl ester metal chelate compound isa 6,8-dimercaptooctanoic acid ethyl ester metal chelate compound.

(5) The melanin eliminator preparation defined in (1) above wherein themetal chelate compound is a N-(6,8-dimercaptooctanoyl)amine metalchelate compound.

(6) The melanin eliminator preparation defined in (5) above wherein theN-(6,8-dimercaptooctanoyl)amine metal chelate compound is selected fromthe group consisting of 6,8-dimercaptooctanoic acid amide metal chelate,N-(6,8-dimercaptooctanoyl)-2-aminoethanol metal chelate,N-(6,8-dimercaptooctanoyl)isopropylamine metal chelate,N-(6,8-dimercaptooctanoyl)melatonin metal chelate, andN-(6,8-dimercaptooctanoyl)-2-aminopyridine metal chelate.

(7) The melanin eliminator preparation defined in (1) above wherein themetal chelate compound is a N-(6,8-dimercaptooctanoyl)amino acid metalchelate compound.

(8) The melanin eliminator preparation defined in (7) above wherein theN-(6,8-dimercaptooctanoyl)amino acid metal chelate compound is selectedfrom the group consisting of N-(6,8-dimercaptooctanoyl)-α-amino acidmetal chelate, N-(6,8-dimercaptooctanoyl)-ω-amino acid metal chelate,and N-(6,8-dimercaptooctanoyl)-special amino acids metal chelatecompound.

(9) The melanin eliminator preparation defined in (8) above wherein theN-(6,8-dimercaptooctanoyl)-α-amino acid metal chelate is selected fromthe group consisting of N-(6,8-dimercaptooctanoyl) glycine metalchelate, N-(6,8-dimercaptooctanoyl)alanine metal chelate,N-(6,8-dimercaptooctanoyl)threonine metal chelate,N-(6,8-dimercaptooctanoyl)serine metal chelate,N-(6,8-dimercaptooctanoyl)aspartic acid metal chelate,N-(6,8-dimercaptooctanoyl)glutamic acid metal chelate,N-(6,8-dimercaptooctanoyl)phenylalanine metal chelate,N-(6,8-dimercaptooctanoyl)methionine metal chelate,N-(6,8-dimercaptooctanoyl)norleucine metal chelate,N-(6,8-dimercaptooctanoyl)cysteine metal chelate,N-(6,8-dimercaptooctanoyl)-hydroxyproline metal chelate,N-(6,8-dimercaptooctanoyl)histidine metal chelate,N-(6,8-dimercaptooctanoyl)-5-hydroxytryptophan metal chelate,N-(6,8-dimercaptooctanoyl)penicillamine metal chelate andN-(6,8-dimercaptooctanoyl)lysine metal chelate compounds.

(10) The melanin eliminator preparation defined in (9) above wherein theN-(6,8-dimercaptooctanoyl)-ω-amino acid metal chelate and theN-(6,8-dimercaptooctanoyl)special amino acid metal chelate compounds areselected from the group consisting ofN-(6,8-dimercaptooctanoyl)-3-aminopropionic acid metal chelate,N-(6,8-dimercaptooctanoyl)-4-aminobutyric acid metal chelate,N-(6,8-dimercaptooctanoyl)-6-aminohexanoic acid metal chelate,N-(6,8-dimercaptooctanoyl)-4-trans-aminomethyl-1-cyclohexane carboxylicacid metal chelate, N-(6,8-dimercaptooctanoyl)-2-aminoethanesulfonicacid metal chelate, N-(6,8-dimercaptooctanoyl)sulfanilic acid metalchelate, N-(6,8-dimercaptooctanoyl)anthranilic acid metal chelate andN-(6,8-dimercaptooctanoyl)anthranilic acid ethyl ester metal chelatecompounds.

(11) The melanin eliminator preparation defined in (1) above wherein themetal chelate compound is a N-(6,8-dimercaptooctanoyl)peptide metalchelate compound.

(12) The melanin eliminator preparation defined in (11) above whereinthe N-(6,8-dimercaptooctanoyl)peptide metal chelate compound is selectedfrom the group consisting of N-(6,8-dimercaptooctanoyl)-aspartylglycinemetal chelate and N-(6,8-dimercaptooctanoyl)threonylglycine metalchelate.

(13) The melanin eliminator preparation defined in one of (1) to (12)above wherein the metal is zinc.

(14) The melanin eliminator preparation defined in one of (1) to (13)above wherein the preparation is a dermatological preparation forexternal use.

(15) The melanin eliminator preparation defined in (14) above whereinthe preparation is a cosmetic preparation.

(16) A zinc chelate compound represented by the following formula (II),

wherein R denotes hydroxyl, O-alkyl, an amine bonded at N or a peptidebonded at N, or a pharmacologically acceptable salt thereof.

(17) The zinc chelate compound defined in (16) above wherein thecompound is a 6,8-dimercaptooctanoic acid zinc chelate compound, or apharmacologically acceptable salt thereof.

(18) A method for elimination of melanin comprising administering to ahuman an effective amount of a metal chelate compound represented by thefollowing formula (I),

wherein M denotes a metal, and R denotes hydroxyl, O-lower alkyl, anamine bonded at N, an amino acid bonded at N or a peptide bonded at N,or a pharmacologically acceptable salt thereof.

(19) Use of a metal chelate compound represented by the followingformula (I),

wherein M denotes a metal, and R denotes hydroxyl, O-lower alkyl, anamine bonded at N, an amino acid bonded at N or a peptide bonded at N,or a pharmacologically acceptable salt thereof for the manufacture of amelanin eliminating preparation.

BEST MODE FOR CARRYING OUT THE INVENTION

Examples of the metal of the metal chelate compound contained in themelanin eliminator preparation of the present invention include zinc,cobalt, iron and germanium, among which zinc is preferred.

In the present invention, examples of the lower alkyl include linear orbranched alkyl having 1 to 6 carbon atoms, such as methyl, ethyl,propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl,isopentyl, neopentyl, tert-pentyl, hexyl, 2-methylpentyl,3-methylpentyl, 4-methylpentyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl,2-ethylbutyl, etc. among which methyl and ethyl are preferred.

In the present invention, an “amine” means a compound obtained byreplacing 1-2 hydrogen atoms of ammonia NH₃ with an aliphatichydrocarbon group having 1-5 carbon atoms that may be substituted with ahydroxyl group, or a compound obtained by replacing 1-2 hydrogen atomsof ammonia with a nitrogen-containing hetero ring including pyridinering, a pyrimidine ring or an indole ring that may be substituted.Specifically, 2-aminoethanol, isopropylamine, melatonin,2-aminopyridine, etc. are included.

In the present invention, an “amino acid” means a ω-amino acid having acarboxyl group and an amino acid in the same molecule, such as α-aminoacid, β-amino acid, γ-amino acid, δ-amino acid, ε-amino acid, etc., sucha special amino acid as aminomethylcyclohexanecarboxylic acid,anthranilic acid and anthranilic acid ethyl ester, as well as a specialamino acid that has a sulfonic acid group and an amino acid in the samemolecule such as aminoethanesulfonic acid (taurine) andp-aminobenzenesulfonic acid (sulfanilic acid). Examples of α-amino acidinclude glycine, alanine, valine, leucine, isoleucine, serine,threonine, tyrosine, cysteine, methionine, aspartic acid, asparagine,glutamic acid, glutamine, arginine, lysine, histidine, phenylalanine,tryptophan, etc. Examples of β-amino acid include β-alanine, examples ofγ-amino acid include γ-amino-L-butyric acid (GABA) and carnitine.Examples of δ-amino acid include 5-aminolevulinic acid and5-aminovaleric acid. Examples of ε-amino acid include 6-aminohexanoicacid. Among those amino acids, anthranilic acid, aminoethanesulfonicacid, methionine, histidine, lysine, phenylalanine, γ-amino-L-butyricacid and 6-aminohexanoic acid are preferred.

In the present invention, a “peptide” means a dipeptide which is formedfrom two amino acids (as defined above), which may be the same ordifferent, by acid amide bond between a carboxyl group of one amino acidand an amino group of the other amino acid, e.g., aspartylglycine andthreonylglycine, etc.

Examples of a pharmacologically acceptable salt of the present compoundinclude alkali metal salts such as sodium salt and potassium salt, aswell as alkali earth metal salt such as calcium salt and magnesium salt.However, any other salts may be employed as desired for the purpose ofthe present invention insofar as they are pharmacologically acceptable.

Referring for example to a zinc chelate compound, a method forpreparation of 6,8-dimercaptooctanoic acid metal chelate compounds, andtheir derivatives, contained in the melanin eliminator preparation ofthe present invention will be described below.

(wherein R denotes hydroxyl, an O-lower alkyl, an amine bonded at N or apeptide bonded at N)

By reducing an α-lipoic acid or an α-lipoic acid amide with zinc andhydrochloric acid (or acetic acid), 6,8-dimercaptooctanoic acid zincchelate or its amide-form compound, respectively, is synthesized. Inaddition, 6,8-dimercaptooctanoic acid ethyl ester zinc chelate, forexample, is obtained by reduction of α-lipoic acid ethyl ester in thesame manner. Further, as for N-(6,8-dimercaptooctanoyl)amines,N-(6,8-dimercaptooctanoyl)amino acids orN-(6,8-dimercaptooctanoyl)peptides, α-lipoic acid, for example, isdissolved in chloroform or acetonitrile, and then coupled with an amine,amino acid or peptide by the mixed acid anhydride method using ethylchloroformate in the presence of triethylamine to form N-α-lipoylamine,N-α-lipoylamino acid or N-α-lipoylpeptide. Reduction of them with zincand acetic acid (or hydrochloric acid) gives the respective aimedcompounds. Furthermore, where the amino acid or peptide derivatives areto be converted to alkali salts, for example, their free acids aredissolved, or suspended in water and then dissolved throughneutralization with alkali hydroxide. Condensation followed bycollection by filtration of crystals precipitated after addition ofalcohol gives the salt of the aimed compounds in high yield.

Reduced form compounds of α-lipoic acids and α-lipoic acid derivatives,i.e., 6,8-dimercaptooctanoic acids and their derivatives, are veryunstable in the air. However, chelation of them with a metal, e.g.,zinc, results in the formation of a six-membered ring and givescrystalline, stable compounds. The present compound, furthermore, has apotent reducing activity as well as a potent radical scavengingactivity, and, as originating from the living body, it is a highly safecompound.

According to the mechanism of formation of melanin, which makes thebasis of blotches and freckles, free radicals are first produced in theskin by the action of ultraviolet light, stimulation by this thenactivates melanocytes, thus activating the function of tyrosinase in themelanocytes, and this leads to melanin formation through severalchemical steps including oxidation and polymerization of tyrosine. Theaction of most skin whitening agents are prevention of melanin formationby their inhibitory effect on the enzyme tyrosinase.

However, as a result of the studies, the present inventor found that thepresent compound has an effect to eliminate already-formed and depositedaggregated melanin pigment (blotches, freckles, lentigines). Thus, thiseffect is considered to be based on a mechanism other than tyrosinaseinhibitory action or elastase inhibitory action.

There are several methods for removing lentigines, such as surgicaloperation, potassium hydroxide/starch or liquid nitrogen method, etc.,all of which give damages to the skin. In recent years, a method isknown in which selective destruction of melanin-containing cells iscaused with laser. However, as laser treatment itself causesinflammation during irradiation, this entails concerns of recurrence.

For the purpose of eliminating melanin, the compound of the presentinvention is applied in the form of ointments, cosmetic preparations orlotions.

According to the observations of the healing effect of the presentcompound, there are cases in which melanin pigment gradually fades incolor from black to pale umber and the other cases in which melaninmigrates to the corneal layer of epidermis and finally lost with thedirt on the skin. If this means that the melanin in the cells isrecognized as a xenobiotic and pushed out as a result of enhancedimmunity, it also suggests a possible application to cancer cells.

Though it depends on the degree of the blotches or lentigines, asevident from the examples described below, the effect of the presentcompound was observed, i.e., for example, a lotion containing 0.5 (w/w)%of N-(6,8-dimercaptooctanoyl)-3-aminopropionic acid sodium/zinc chelateor N-(6,8-dimercaptooctanoyl)anthranilic acid sodium/zinc chelatecompound applied one or two times daily showed satisfactory effects inabout one month, exhibiting either fading of the color from black topale umber or falling off as a scab in the cases of blotches andlentigines located closest to the corneal layer of epidermis, though inthe case of lentigines it depended on which area they were placed, e.g.,on the face, arms, etc. The effect was also noted on blotches formed onthe acne scars, showing clear difference compared with the pre-treatmentconditions.

These findings revealed that the present compound has the activity ofeliminating melanin pigment.

Concentrations of the present compound in use are usually 0.001-5(w/w)%, and preferably 0.01-1.0 (w/w)% in the case of a cream, andusually 0.001-5 (w/v)%, and preferably 0.01-1.0 (w/v)% in the case of anaqueous solution or a lotion.

Ingredients usually employed in cosmetics or dermatological externalpreparations, e.g., diluents, pigments, perfume materials, ultravioletlight absorbents, antioxidants, stabilizers, preservatives, etc. may beadded as desired to the melanin eliminator preparation of the presentinvention.

As desired and in accordance with the purpose and need, the melanineliminator preparation of the present invention may contain one or morespecies of the present compound in combination.

EXAMPLES

The present invention will be described below referring to ReferenceExamples, examples and Test Examples. However, the present invention isnot limited to those examples.

Reference Examples 1-9, Examples 1-12, and 19, 20 General method forpreparation of N-(6,8-dimercaptooctanoyl)amino acid (or peptide)sodium/zinc chelate compounds

4.2 g (0.02 mol) of DL-α-lipoic acid and 2.4 g (0.023 mol) triethylamineare dissolved in 40 ml of acetonitrile and let stand with stirring at−5° C. To this is gradually added dropwise 2.4 g (0.022 mol) of ethylchloroformate, and 20 minutes after completion of this dropwiseaddition, a solution of 1.0-2.0 g of sodium hydroxide and about 0.023mol of an amino acid (or a peptide) in about 50 ml of methanol (or 70%methanol aqueous solution) is quickly added, and stirring is continuedfor 30 minutes and, for further one hour at room temperature.Evaporation of the solvent under reduced pressure gives a salt ofN-(α-lipoyl)amino acid (or peptide).

To this are then added 50 ml of a 60% acetic acid aqueous solution and2.5 g of zinc powder, and, after 1-5 hours of stirring under heating at50° C., unreacted zinc is separated out by filtration, and the filtrateis concentrated. After addition of water (or methanol), precipitatedcrystals are collected by filtration, and washed with water. Thecrystals are suspended in water and then dissolved at pH 9-10 withaddition of alkali hydroxide in order to form an alkali salt. Insolublematters are removed by filtration and the filtrate is concentrated, and,after addition of alcohol, precipitated crystals are collected byfiltration, they are then recrystallized from a proper solvent, such aswater/alcohol.

Reference Example 1 N-(6,8-dimercaptooctanoyl)glycine sodium/zincchelate compound

Using 4.2 g of DL-α-lipoic acid and 1.9 g of glycine, 3.9 g of whitecrystals of the aimed compound were obtained via N-α-lipoylglycinesodium salt (mp. 218-220° C.). mp: decomp. starting at about. 297° C.TLC, Rf=0.64 (chloroform/methanol/water=5/4/1)

Reference Example 2 N-(6,8-dimercaptooctanoyl)aspartic acidmonosodium/zinc chelate compound

Using 4.2 g of DL-α-lipoic acid and 2.9 g of L-aspartic acid, 4.2 g ofwhite crystals of the aimed compound were obtained viaN-α-lipoylaspartic acid sodium salt (mp. over 300° C.). mp: decomp.starting at about 295° C. TLC, Rf=0.53(chloroform/methanol/water=5/4/1).

Reference Example 3 N-(6,8-dimercaptooctanoyl)methionine zinc chelatecompound

Using 4.2 g of DL-α-lipoic acid and 3.5 g of L-methionine, 2.8 g ofwhite crystals of the aimed compound was obtained viaN-α-lipoylmethionine (mp. 108-109° C.). mp: decomp. starting at about260° C. TLC, Rf=0.82 (n-butanol/acetic acid/water=4/1/2)

Reference Example 4 N-(6,8-dimercaptooctanoyl)cysteine zinc chelatecompound

Using 4.2 g of DL-α-lipoic acid and 2.6 g of L-cysteine, 4.1 g of whitecrystals of the aimed compound were obtained via N-α-lipoylcysteinesodium salt (mp: decomp. starting at about 150° C.). mp: decomp.starting at about 280° C. TLC, Rf=0.71(chloroform/methanol/water=5/4/1).

Reference Example 5 N-(6,8-dimercaptooctanoyl)phenylalanine sodium/zincchelate compound

Using 4.2 g of DL-α-lipoic acid and 3.5 g of L-phenylalanine, 3.9 g ofwhite crystals of the aimed compound were obtained via N-α-phenylalanine(mp. 154-156° C.). mp: decomp. starting at about 270° C. TLC, Rf=0.82(n-butanol/acetic acid/water=4/1/2).

Reference Example 6 N-(6,8-dimercaptooctanoyl)-4-aminobutyric AcidSodium/Zinc Chelate Compound

Using 4.2 g of DL-α-lipoic acid and 2.3 g of 4-aminobutyric acid, 5.2 gof white crystals of the aimed compound were obtained viaN-α-lipoyl-4-aminobutyric acid (mp: decomp. starting at about 235° C.).mp: decomp. starting at about 297° C. TLC, Rf=0.70(chloroform/methanol/water=5/4/1).

Reference Example 7 N-(6,8-dimercaptooctanoyl)-6-aminohexanoic acidsodium/zinc chelate compound

Using 4.2 g of DL-α-lipoic acid and 3.0 g of 6-aminohexanoic acid, 2.0 gof white crystals of the aimed compound were obtained viaN-α-lipoyl-6-aminohexanoic acid sodium salt (mp. 200-202° C.). mp:decomp. starting at about 295° C. TLC, Rf=0.84(chloroform/methanol/water=5/4/1).

Reference Example 8 N-(6,8-dimercaptooctanoyl)anthranilic acidsodium/zinc chelate compound

Using 4.2 g of DL-α-lipoic acid and 2.9 g of anthranilic acid, 2.1 g ofwhite crystals of the aimed compound were obtained viaN-α-lipoylanthranilic acid sodium salt (mp. over 300° C.). mp: decomp.starting at about 290° C. TLC, Rf=0.88 (n-butanol/aceticacid/water=4/1/2).

Reference Example 9 N-(6,8-dimercaptooctanoyl)-2-aminoethanesulfonicacid sodium/zinc chelate compound

Using 6.2 g of DL-α-lipoic acid and 4.5 g of 2-aminoethanesulfonic acid,4.5 g of white crystals of the aimed compound were obtained viaN-α-lipoylaminoethanesulfonic acid sodium salt (mp. 235-237° C.). mp:decomp. starting at about 293° C. TLC, Rf=0.51 (n-butanol/aceticacid/water=4/1/2).

Example 1 N-(6,8-dimercaptooctanoyl)hydroxyproline sodium/zinc chelatecompound

From 4.2 g of DL-α-lipoic acid and 2.8 g of L-4-hydroxyproline, 4.9 g ofwhite crystals of the aimed compound were obtained. mp. over 300° C.TLC, Rf=0.66 (n-butanol/acetic acid/water=4/1/2).

Example 2 N-(6,8-dimercaptooctanoyl)histidine sodium/zinc chelatecompound

From 4.2 g of DL-α-lipoic acid and 3.4 g of L-histidine, 5.8 g of whitecrystals of the aimed compound were obtained. mp. over 300° C. TLC,Rf=0.39 (n-butyanol/acetic acid/water=4/1/2). mp. over 300° C., TLC,Rf=0.39 (n-butanol/acetic acid/water=4/1/2).

Example 3 N-(6,8-dimercaptooctanoyl)glutamic Acid sodium/zinc chelatecompound

From 4.2 g of DL-α-lipoic acid and 3.5 g of L-glutamic acid, 5.7 g ofwhite crystals of the aimed compound were obtained. mp. over 300° C.TLC, Rf=0.74 (n-butanol/acetic acid/water=4/1/2).

Example 4 N-(6,8-dimercaptooctanoyl)threonine sodium/zinc chelatecompound

From 4.2 g of DL-α-lipoic acid and 2.6 g of L-threonine, 5.5 g of whitecrystals of the aimed compound were obtained. mp. over 300° C. TLC,Rf=0.73 (n-butanol/acetic acid/water=4/1/2).

Example 5 N-(6,8-dimercaptooctanoyl)alanine sodium/zinc chelate compound

From 4.2 g of DL-α-lipoic acid and 2.1 g of L-alanine, 5.4 g of whitecrystals of the aimed compound were obtained. mp: decomp. starting atabout 290° C. TLC, Rf=0.78 (n-butanol/acetic acid/water=4/1/2).

Example 6 N-(6,8-dimercaptooctanoyl)serine sodium/zinc chelate compound

From 4.2 g of DL-α-lipoic acid and 2.4 g of L-serine, 5.0 g of whitecrystals of the aimed compound were obtained. mp: gradual decomp.starting at about 285° C. TLC, Rf=(n-butanol/acetic acid/water=4/1/2).

Example 7 N-(6,8-dimercaptooctanoyl)norleucine sodium/zinc chelatecompound

From 4.2 g of DL-α-lipoic acid and 3.0 g of L-norleucine, 5.1 g of whitecrystals of the aimed compound were obtained. mp. gradual decomp.starting at about 295° C. TLC, Rf=0.90 (n-butanol/aceticacid/water=4/1/2).

Example 8 N-(6,8-dimercaptooctanoyl)-5-hydroxytryptophan sodium/zincchelate compound

From 4.2 g of DL-α-lipoic acid and 5.0 g of L-5-hydroxytryptophan, 6.5 gof grayish white crystals of the aimed compound were obtained. mp:decomp. starting at about 290° C. TLC, Rf=0.81 (n-butanol/aceticacid/water=4/1/2).

Example 9 N-(6,8-dimercaptooctanoyl)penicillamine sodium/zinc chelatecompound

From 4.2 g of DL-α-lipoic acid and 3.5 g of penicillamine, 6.0 g ofwhite crystals of the aimed compound were obtained. mp: gradual decomp.starting at about 280° C. TLC, Rf=0.80 (n-butanol/aceticacid/water=4/1/2).

Example 10 N-(6,8-dimercaptooctanoyl)-3-aminopropionic acid sodium/zincchelate compound

From 4.2 g of DL-α-lipoic acid and 2.0 g of β-alanine, 5.8 g of whitecrystals of the aimed compound were obtained. mp: gradual decomp.starting at about 295° C. TLC, Rf=0.83 (n-butanol/aceticacid/water=4/1/2).

Example 11N-(6,8-dimercaptooctanoyl)-4-transaminomethyl-1-cyclohexanecarboxylicacid sodium/zinc chelate compound

From 4.2 g of DL-α-lipoic acid and 3.5 g of4-trans-aminomethylcyclohexanecarboxylic acid, 5.8 g of white crystalsof the aimed compound were obtained. mp: gradual decomp. starting atabout 297° C. TLC, Rf=0.81 (n-butanol/acetic acid/water=4/1/2).

Example 12 N-(6,8-dimercaptooctanoyl)sulfanilic acid sodium/zinc chelatecompound

From 4.2 g of DL-α-lipoic acid and 3.8 g of sulfanilic acid, 5.4 g ofwhite crystals of the aimed compound were obtained. mp. over 300° C.TLC, Rf=0.57 (n-butanol/acetic acid/water=4/1/2).

Example 13 N-(6,8-dimercaptooctanoyl)isopropylamine zinc chelatecompound

4.2 g of DL-α-lipoic acid and 2.4 g of triethylamine were dissolved in50 ml of acetonitrile and cooled down to −5° C. with stirring. To thiswas gradually added 2.4 g of ethyl chloroformate dropwise. Twentyminutes after the completion of the dropwise addition, 1.5 g ofisopropylamine dissolved in 30 ml of acetonitrile was quickly added, andstirring was continued for 30 minutes and, further one hour at roomtemperature. The solvent was evaporated under reduced pressure, andwater was added to the residue and the mixture then was cooled down.Precipitated pale yellow crystals were collected by filtration,dissolved in 60 ml of tetrahydrofuran (THF). To this were added 20 ml of50% acetic acid aqueous solution and 2.0 g of zinc powder and reactionwas allowed for two hours at 50° C. with stirring. Unreacted zinc wasseparated out by filtration, and the filtrate was concentrated. Afteraddition of water to the residue, precipitated white crystals werecollected by filtration. Recrystallized from THF/acetic acid/water gave5.0 g of the aimed compound. mp. 271-273° C. TLC, Rf=0.89(n-butanol/acetic acid/water=4/1/2).

Example 14 N-(6,8-dimercaptooctanoyl)-2-aminoethanol zinc chelatecompound

Using 4.2 g of DL-α-lipoic acid and 1.5 g of monoethanolamine, 4.2 g ofwhite crystals of the aimed compound were obtained by the same method asin Example 13. mp: gradual decomp. starting at about 298° C. TLC,Rf=0.77 (n-butanol/acetic acid/water=4/1/2).

Example 15 N-(6,8-dimercaptooctanoyl)melatonin zinc chelate compound

Using 4.2 g of DL-α-lipoic acid and 4.0 g of melatonin, 6.5 g of whitecrystals of the aimed compound were obtained by the same method as inExample 13. mp. 210-212° C. TLC, Rf=0.84 (n-butanol/aceticacid/water=4/1/2).

Example 16 N-(6,8-dimercaptooctanoyl)-2-aminopyridine zinc chelatecompound

Using 4.2 g of DL-α-lipoic acid and 2.2 g of 2-aminopyridine, 5.3 g ofwhite crystals of the aimed compound were obtained by the same manner asin Example 13. mp. 243-245° C. TLC, Rf=0.87 (n-butanol/aceticacid/water=4/1/2).

Example 17 N-(6,8-dimercaptooctanoyl)anthranilic acid ethyl ester zincchelate compound

Using 4.2 g of DL-α-lipoic acid and 3.6 g of anthranilic acid ethylester, 4.6 g of white crystals of the aimed compound (recrystallizedfrom THF/acetic acid/water) were obtained. mp. gradual decomp. startingat about 290° C. TLC, Rf=0.88 (n-butanol/acetic acid/water).

Example 18 N^(ε)-(6,8-dimercaptooctanoyl)lysine zinc chelate compound

A mixed acid anhydride was prepared from 4.2 g of DL-α-lipoic acid, 2.4g of triethylamine and 2.4 g of ethyl chloroformate in 50 ml ofacetonitrile under cooling. To this were added a solution of 3.1 g ofL-lysine, 5.5 g of copper sulfate (pentahydrate) and 2.0 g of sodiumhydroxide in 60 ml of water, and reaction was allowed. PrecipitatedN^(ε)-(α-lipoyl)lysine cupper salt was collected by filtration, andwashed with water and methanol. This was suspended in 70% acetic acidaqueous solution and cupper was converted to copper sulfide withhydrogen sulfide and removed by filtration. The filtrate wasconcentrated, methanol was added to the residue, and precipitated paleyellow crystals were collected by filtration. mp. 254-255° C., Yield:3.5 g.

This was then dissolved in 60% acetic acid aqueous solution and 2.0 g ofzinc powder was added. After 3 hours of stirring at 50° C. and removalof the zinc by filtration, the filtrate was concentrated. Addition ofmethanol to this and collection of precipitated white crystals byfiltration gave 3.4 of the aimed compound. mp. gradual decomp. startingat about 295° C. TLC, Rf=0.47 (n-butanol/acetic acid/water=4/1/2).

Example 19 N-(6,8-dimercaptooctanoyl)aspartylglycine disodium/zincchelate compound

Using 2.1 g of DL-α-lipoic acid and 2.1 g of L-aspartylglycine, 3.1 g ofwhite crystals of the aimed compound were obtained viaN-(α-lipoyl)aspartylglycine sodium salt in the same manner. mp: gradualdecomp starting at about 270° C. TLC, Rf=0.54 (n-butanol/aceticacid/water=4/1/2).

Example 20 N-(6,8-dimercaptooctanoyl)threonylglycine sodium/zinc chelatecompound

Using 2.1 g of DL-α-lipoic acid and 2.1 g of L-threonylglycine, 2.6 g ofpale yellow crystals of the aimed compound were obtained. mp: gradualdecomp. starting at about 260° C. TLC, Rf=0.60 (n-butanol/aceticacid/water=4/1/2).

Example 21 6,8-dimercaptooctanoic Acid ethanolamine salt zinc chelatecompound (also named as dihydrolipoic acid monoethanolamine salt zinccomplex)

6.2 g of DL-α-lipoic acid was dissolved in 70 ml of methanol, and tothis were added 3.5 g of zinc powder and 15 ml of 2 N hydrochloric acidand stirred for one hour at 50° C. When the solution turned colorless,unreacted zinc was removed by filtration, and the filtrate wasconcentrated under reduced pressure. Addition of 150 ml of water to theoily residue, collection of thus precipitated white crystals byfiltration and washing with water gave the free acid form of6,8-dimercaptooctanoic acid zinc chelate compound.

The free acid was suspended in 150 ml of water. To this was added about2.5 g of monoethanolamine to dissolve. Concentration under reducedpressure, addition of ethanol to the oily residue thus obtained,collection of precipitated white crystals by filtration,recrystallization from water/ethanol gave 8.5 g of the aimed compound.mp. 137-139° C.

Example 22 6,8-dimercaptooctanoic acid sodium salt zinc chelate compound

6.2 g of DL-α-lipoic acid was dissolved in 70 ml of methanol, and tothis were added 3.0 g of zinc powder and 40 ml of 1 N hydrochloric acid,and stirred for one hour at 50° C. Unreacted zinc was separated out byfiltration. The filtrate was concentrated under reduced pressure andwater was added. Precipitated white crystals were collected byfiltration. They were suspended in 150 ml of water and dissolved at a pHof about 9 by addition of 2 N sodium hydroxide. Insoluble matters wereremoved by filtration and the filtrate was concentrated. Addition ofethanol to this, collection of precipitated white crystals byfiltration, and recrystallized from water/ethanol gave 6.0 g of theaimed compound. mp. over 300° C. TLC, Rf=0.88 (n-butanol/aceticacid/water=4/1/2).

Example 23 6,8-dimercaptooctanoic acid ethyl ester zinc chelate compound

3.5 g of DL-α-lipoic acid ethyl ester was dissolved in 60 ml oftetrahydrofuran, and to this were added 2.0 g of zinc powder and 40 mlof 70% acetic acid aqueous solution and stirred for two hours at 50° C.Unreacted zinc was separated out by filtration, the filtrate wasconcentrated, and water was added to this. Precipitated white crystalswere collected by filtration. Recrystallized from acetic acid/water gave3.6 g of the aimed compound. mp: gradual decomp. starting at about 290°C. TLC, Rf=0.88 (n-butanol/acetic acid/water=4/1/2).

Example 24 6,8-dimercaptooctanoic acid amide zinc chelate compound

4.2 g of DL-α-lipoic acid amide was dissolved in 70 ml oftetrahydrofuran. To this were added 2.5 g of zinc powder and 30 ml of50% acetic acid aqueous solution and stirred for two hours at 50° C.Evaporation of the solvent, collection of precipitated crystalscontaining zinc, washing with water and ethanol, and recrystallizationfrom acetic acid/water gave 4.5 g of white crystals. mp. 257-259° C.TLC, Rf=0.80 (n-butanol/acetic acid/water=4/1/2).

Preparation examples will be presented below. Preparation Example 1Toilet water The compound of Reference Example 8   0.5 g Glycerol   3.5g Methyl p-hydroxybenzoate   0.02 g Propyl p-hydroxybenzoate   0.01 gSterile purified water  to 100 ml Preparation Example 2 Toilet water Thecompound of Reference Example 10   0.5 g Propylene glycol   3.0 g Tego51  0.005 g Sterile purified water  to 100 ml Preparation Example 3Cream preparation The compound of Example 11   0.1 g Stearic acid   2.0g Stearyl alcohol   7.0 g Squalane   5.0 g Octyldecanol   6.0 gPolyoxyethylene cetyl ether   3.0 g Glyceryl monostearate   2.0 gPropylene glycol   5.0 g Methyl p-hydroxybenzoate   0.05 g Propylp-hydroxybenzoate   0.02 g Sterile purified water  to 100 g PreparationExample 4 Ointment The compound of Reference Example 7   1.0 gHydrophilic ointment  to 100 g Preparation Example 5 The compound ofExample 22   0.5 g Pantothenyl alcohol   0.5 g Glycerol   2.5 g Tego-51 0.007 g Sterile purified water  to 100 ml

With reference to test examples below, the effect of the presentinvention will be demonstrated. It should be noted, however, that theyare no more than illustration by examples and not intended to limit thescope of the present invention.

Test Example 1

To blotches and freckles on the face, the toilet water shown inPreparation Example 1 was applied once daily for one month. As a result,notable effect was observed in comparison with the pre-applicationcondition, including cases of nearly disappearance and cases of fadingin color to pale umber.

Test Example 2

To blotches formed on acne scars in the face, the preparation ofPreparation Example 2 was applied for a month in the same manner as inTest Example 1. As a result, the blotches nearly disappeared incomparison with the pre-application condition.

Test Example 3

To deposited melanin pigment on a part of the lips, the preparation ofPreparation Example 5 was applied once daily. Three months later, theblack color was found eliminated.

Test Example 4

To the backs of hands which were sunburned on the seashore for twostraight days, the preparation of Preparation Example 5 was applied oncedaily after their inflammation subsided. One month later, their color,which had been dark due to the suntan, returned to their pre-suntantone.

Test Example 5

To a lentigo (1-mm diameter) on the arm was topically applied twicedaily a preparation that was prepared according to Preparation Example 1except that N-(6,8-dimercaptooctanoyl)histidine sodium/zinc chelate ofExample 2 was used instead of N-(6,8-dimercaptooctanoyl)anthranilic acidsodium/zinc chelate of Example 2. Two months later, the black color wasfound eliminated leaving a subtle scar behind.

INDUSTRIAL APPLICABILITY

The present compound, 6,8-dimercaptooctanoic acid zinc chelate, itsderivatives and their pharmacologically acceptable salts exhibitexcellent therapeutic effects in elimination of melanin pigment. Thus,they are useful in providing melanin eliminator preparations.

Some of the embodiments of the present invention were described indetail above. As it is readily possible for a person skilled in the artto make a variety of modifications and alterations to the shownembodiments without substantially departing from the novel teachings andadvantages the present invention, all of such modifications andalterations are also included in the spirit and scope of the presentinvention that is defined by the claims below.

The present invention is based on the patent application No. 2002-307643filed in Japan, the content of which is included in its entirety in thedescription of the present application.

1. A melanin eliminator preparation comprising a metal chelate compoundrepresented by the following formula (I),

wherein M denotes a metal, and R denotes hydroxyl, O-lower alkyl, anamine bonded at N, an amino acid bonded at N, or a peptide bonded at N,or a pharmacologically acceptable salt thereof.
 2. The melanineliminator preparation of claim 1 wherein the metal chelate compound is6,8-dimercaptooctanoic acid metal chelate compound.
 3. The melanineliminator preparation of claim 1 wherein the metal chelate compound isa 6,8-dimercaptooctanoic acid lower alkyl ester metal chelate compound.4. The melanin eliminator preparation of claim 3 wherein the6,8-dimercaptooctanoic acid lower alkyl ester metal chelate compound isa 6,8-dimercaptooctanoic acid ethyl ester metal chelate compound.
 5. Themelanin eliminator preparation of claim 1 wherein the metal chelatecompound is a N-(6,8-dimercaptooctanoyl)amine metal chelate compound. 6.The melanin eliminator preparation of claim 5 wherein theN-(6,8-dimercaptooctanoyl)amine metal chelate compound is selected fromthe group consisting of 6,8-dimercaptooctanoic acid amide metal chelate,N-(6,8-dimercaptooctanoyl)-2-aminoethanol metal chelate,N-(6,8-dimercaptooctanoyl)isopropylamine metal chelate,N-(6,8-dimercaptooctanoyl)melatonin metal chelate, andN-(6,8-dimercaptooctanoyl)-2-aminopyridine metal chelate.
 7. The melanineliminator preparation claim 1 wherein the metal chelate compound is aN-(6,8-dimercaptooctanoyl)amino acid metal chelate compound.
 8. Themelanin eliminator preparation of claim 7 wherein theN-(6,8-dimercaptooctanoyl)amino acid metal chelate compound is selectedfrom the group consisting of N-(6,8-dimercaptooctanoyl)-α-amino acidmetal chelate, N-(6,8-dimercaptooctanoyl)-ω-amino acid metal chelate,and N-(6,8-dimercaptooctanoyl)-special amino acids metal chelatecompound.
 9. The melanin eliminator preparation of claim 8 wherein theN-(6,8-dimercaptooctanoyl)-α-amino acid metal chelate is selected fromthe group consisting of N-(6,8-dimercaptooctanoyl) glycine metalchelate, N-(6,8-dimercaptooctanoyl)alanine metal chelate,N-(6,8-dimercaptooctanoyl)threonine metal chelate,N-(6,8-dimercaptooctanoyl)serine metal chelate,N-(6,8-dimercaptooctanoyl)aspartic acid metal chelate,N-(6,8-dimercaptooctanoyl)glutamic acid metal chelate,N-(6,8-dimercaptooctanoyl)phenylalanine metal chelate,N-(6,8-dimercaptooctanoyl)methionine metal chelate,N-(6,8-dimercaptooctanoyl)norleucine metal chelate,N-(6,8-dimercaptooctanoyl)cysteine metal chelate,N-(6,8-dimercaptooctanoyl)hydroxyproline metal chelate,N-(6,8-dimercaptooctanoyl)histidine metal chelate,N-(6,8-dimercaptooctanoyl)-5-hydroxytryptophan metal chelate,N-(6,8-dimercaptooctanoyl)penicillamine metal chelate andN-(6,8-dimercaptooctanoyl)lysine metal chelate compounds.
 10. Themelanin eliminator preparation of claim 9 wherein theN-(6,8-dimercaptooctanoyl)-ω-amino acid metal chelate and theN-(6,8-dimercaptooctanoyl)special amino acid metal chelate compounds areselected from the group consisting ofN-(6,8-dimercaptooctanoyl)-3-aminopropionic acid metal chelate,N-(6,8-dimercaptooctanoyl)-4-aminobutyric acid metal chelate,N-(6,8-dimercaptooctanoyl)-6-aminohexanoic acid metal chelate,N-(6,8-dimercaptooctanoyl)-4-trans-aminomethyl-1-cyclohexane carboxylicacid metal chelate, N-(6,8-dimercaptooctanoyl)-2-aminoethanesulfonicacid metal chelate, N-(6,8-dimercaptooctanoyl)sulfanilic acid metalchelate, N-(6,8-dimercaptooctanoyl)anthranilic acid metal chelate andN-(6,8-dimercaptooctanoyl)anthranilic acid ethyl ester metal chelatecompounds.
 11. The melanin eliminator preparation claim 1 the metalchelate compound is a N-(6,8-dimercaptooctanoyl)peptide metal chelatecompound.
 12. The melanin eliminator preparation claim 11 wherein theN-(6,8-dimercaptooctanoyl)peptide metal chelate compound is selectedfrom the group consisting of N-(6,8-dimercaptooctanoyl)aspartylglycinemetal chelate and N-(6,8-dimercaptooctanoyl)threonylglycine metalchelate.
 13. The melanin eliminator preparation of claim 1 wherein themetal is zinc.
 14. The melanin eliminator preparation of claim 1 whereinthe preparation is a dermatological preparation for external use. 15.The melanin eliminator preparation of claim 14 wherein the preparationis a cosmetic preparation.
 16. A zinc chelate compound represented bythe following formula (II),

wherein R denotes hydroxyl, O-alkyl, an amine bonded at N or a peptidebonded at N, or a pharmacologically acceptable salt thereof.
 17. Thezinc chelate compound of claim 16 wherein the compound is a6,8-dimercaptooctanoic acid zinc chelate compound, or apharmacologically acceptable salt thereof.
 18. A method for eliminationof melanin comprising administering to a human an effective amount of ametal chelate compound represented by the following formula (I),

wherein M denotes a metal, and R denotes hydroxyl, O-lower alkyl, anamine bonded at N, an amino acid bonded at N or a peptide bonded at N,or a pharmacologically acceptable salt thereof.
 19. Use of a metalchelate compound represented by the following formula (I),

wherein M denotes a metal, and R denotes hydroxyl, O-lower alkyl, anamine bonded at N, an amino acid bonded at N or a peptide bonded at N,or a pharmacologically acceptable salt thereof for the manufacture of amelanin eliminating preparation.